Mechanism of activation of an ancestral TEC kinase by PIP₃

The TEC kinases are a family of five paralogous mammalian genes that play crucial roles in cell growth, proliferation, and differentiation, particularly in immune cells. The recruitment and activation of the TEC kinases depend on the generation of the lipid second messenger, PIP₃, in the plasma membrane. However, the mechanisms by which PIP₃ activates the TEC kinases are not well understood. By studying an ancestral TEC kinase from the choanoflagellate Monosiga brevicollis, we have elucidated an evolutionarily conserved mechanism for the activation of the TEC kinases by PIP₃. We demonstrate that PIP₃, but not PIP₂, relieves autoinhibition by displacing the PH domain of MbTEC from a conserved intramolecular interaction with its kinase domain. We also show that a conserved polyproline motif within MbTEC promotes its activation in a kinase-intrinsic mechanism. Finally, we show that the PH domain is sufficient to restore autoinhibition in a constitutively active mutant of MbTEC. Our findings reveal that PIP₃ is necessary but not sufficient for MbTEC activation.